The present invention relates to quinolonecarboxylic acid derivatives having more excellent and broad antibacterial activities than the existing quinolone-series antibiotics. More specifically, it pertains to novel quinolonecarboxylic acid derivatives represented by following formula 1, which have a derivative of 7-[8-(alkoxyimino)-2,6-diazaspiro[3.4]oct-6-yl] as a substituent, and pharmaceutically acceptable salts and isomers thereof: 
Wherein, A is Cxe2x80x94H, Cxe2x80x94F, Cxe2x80x94Cl, Cxe2x80x94Oxe2x80x94CH13 or N; Y is H or amino; R1 is cyclopropyl or 2,4-difluorophenyl; R2 is C1-4 alkyl; and R3 is H or C1-4 alkyl.
Quinolonecarboxylic acid derivatives are synthetic antibiotics which are well known to be useful for the treatment of infective diseases in human and animals due to their potent and broad antibacterial activities. Quinolone-series antibiotics such as norfloxacin, ofloxacin and ciprofloxacin are currently used very usefully for the treatment of human diseases and their efficacies are acknowledged. However, these medicines have a problem that: even though they show excellent antibacterial activities against gram-negative bacteria, they still show ordinary or relatively low antibacterial activities against gram-positive bacteria. Accordingly, there have been various studies for solving such problems of existing quinolone-series antibiotics and, finally, sparfloxacin having improved antibacterial activities against gram-positive bacteria has been developed.
However, this compound still shows weak antibacterial activities against Streptococci, methicillin resistant Staphylococcus aureus(MRSA) and other currently increasing quinolone-resistant strains. These strains are well known as pathogens of the respiratory infections. Therefore, there are increasing needs for the development of improved quinolone antibiotics which exhibit excellent antibacterial activities against such quinolone-resistant strains.
On the other hand, Korean patent laid-open publication Nos. 96-873, 96-22501 and 96-22502, and EP688772A1 disclose quinolone-series antibacterial agents of following formulae 16, 17 and 18: 
Wherein, Q is Cxe2x80x94H, Cxe2x80x94F, Cxe2x80x94Cl, Cxe2x80x94OH, Cxe2x80x94Oxe2x80x94CH3 or N; R is H, methyl or amino; R1 is cyclopropyl, ethyl, or phenyl substituted with more than one fluorine atom; R2 is H, C1-4 straight or branched alkyl, phenyl or allyl. 
Wherein, R is H, methyl or amino; Q is Cxe2x80x94H, Cxe2x80x94F, Cxe2x80x94Cl, Cxe2x80x94CH3, Cxe2x80x94Oxe2x80x94CH3 or N; R1 is cyclopropyl, ethyl, or phenyl substituted with one or more fluorine atoms; R2 is C3-C4 branched alkyl such as t-butyl and cyclopropylmethyl, C3-C6 alkyl having a triple bond such as propagyl and homopropagyl, 2-haloethyl, methoxymethyl, methoxycarbonylmethyl, or a group having the following formula: 
Wherein, n is 0 or 1; m is 0, 1 or 2; x is methylene, O or N; R3 and R4 are independently H or C1-C3 alkyl group, or they may form a ring with a nitrogen group to which they are attached. 
Wherein,
R is H, methyl or amino group;
Q is Cxe2x80x94H, Cxe2x80x94F, Cxe2x80x94Cl, Cxe2x80x94CH3, Cxe2x80x94Oxe2x80x94CH3 or N;
R1 is cyclopropyl, ethyl, or phenyl group substituted with one or more fluorine atom;
R2 is a group of following formula a: 
Wherein, X is 2-, 3- or 4-fluoro, cyano, nitro, methoxy, methyl or C1-C4 alkyl group, or 2,4-difluoro group;
a group of following formula b: 
an arylmethyl group containing a hetero group of following formula c: 
R3 and R4 are independently H or C1-C3 alkyl group, or they may form a ring with a nitrogen group to which they are attached.
The above compounds are different from the compound of the present invention of the formula 1 in their structures. Specifically, in the compounds disclosed in Korean Patent laid-open publication Nos. 96-873, 96-22501 and 96-22502, and EP688772 A1, an alkoxyimino group is substituted on the pyrrolidine ring, which is a substituent at the 7-position, and the substituents adjacent to the alkoxyimino group such as amino, alkylamino, aminomethyl, alkylaminomethyl are attached to the pyrrolidine ring as a straight chain form. In contrast, in the compounds of the present invention, the pyrrolidine ring substituted at the 7-position having an oxime and its derivatives, forms a diazaspiro compound with an azetidine structure. Accordingly, the compounds of the present invention are different from those of the above patent laid-open publications in their structures. In terms of antibacterial activities, the compounds of the present invention show strong antibacterial activities against the recently-increasing quinolone-resistant strains, while the compounds of the above patent laid-open publications exhibit very weak antibacterial activities against the quinolone-resistant strains.
Further, although EP265230 A1 discloses the substitution of diazaspiro compound at 7-position of the quinolone derivative, it specifically discloses only 2,7-diazaspiro[4.4]nonane and 2-methyl-2,7-diazaspiro[4.4]nonane compounds of the following formulae and does not specifically disclose 2,6-diazaspiro[3.4]octane compound as disclosed in the present invention. Moreover, there is no mention about the alkoxyimino group introduced in the 2,6-diazaspiro[3.4]octane substituent on the 7-position as disclosed in the present invention. Accordingly, the compounds of the present invention are different from those of the above-mentioned patent laid-open publications in terms of structure. As to antibacterial activities, the compounds of the present invention exhibit excellent antibacterial activities against the existing quinolone-resistant strains as well as against both of gram-negative and gram-positive bacteria, while the compounds of the above-mentioned patent laid-open publications have ordinary antibacterial activities against gram-negative and gram-positive bacteria.
The present invention have endeavored constantly to develop novel quinolonecarboxylic acids which exhibit excellent antibacterial activities against both of gram-negative and gram-positive bacteria, as well as improved antibacterial activities against such problematic strains as Streptococci, methicillin resistant Staphylococcus aureus(MRSA) and other currently increasing quinolone-resistant strains.
Finally, the present inventors have accomplished the present invention by discovering that quinolonecarboxylic acids substituted with 7-[8-(alkoxyimino)-2,6-diazaspiro[3.4]oct-6-yl] at the 7-position show excellent antibacterial activities against the above-mentioned strains.
Accordingly, it is an object of the present invention to provide novel quinolonecarboxylic acid derivatives of the above formula 1, and pharmaceutically acceptable salts and isomers thereof, which exhibit excellent antibacterial activities against both of gram-negative and gram-positive bacteria and, especially, show superior antibacterial activities against the methicillin-resistant strains, as well as against the existing quinolone-resistant strains.
Another object of the present invention is to provide processes for preparing the novel quinolonecarboxylic acid derivatives of the formula 1.